[A Case of Synchronous Solitary Splenic Metastasis of Sigmoid Colon Cancer Treated with Laparoscopic Resection].

An 82-year-old woman presented to our hospital with chief complaints of lower abdominal pain and nausea. Contrast- enhanced CT showed ileus of sigmoid colon cancer and a solitary splenic tumor. A metallic stent was placed for the primary lesion. FDG-PET showed high FDG accumulation in the solitary splenic tumor, and synchronous solitary splenic metastasis was diagnosed. Laparoscopic sigmoid colectomy and laparoscopic splenectomy were performed without changing the intraoperative position or port arrangement. Postoperative progress was favorable. The patient was discharged 9 days after surgery, and no sign of recurrence has been observed to date, at 4 months after surgery. Solitary splenic metastasis of colorectal cancer is extremely rare. This is the first case report of synchronous solitary splenic metastasis of colorectal cancer treated with laparoscopic resection in Japan. This procedure is considered effective and minimally invasive. We review and discuss the Japanese literature on this rare disease.

Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor.

Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

Anatomical study of the left superior mediastinal lymphatics for tracheal branches of left recurrent laryngeal nerve-preserving mediastinoscope-assisted surgery in esophageal cancer.

PURPOSE: Curative treatment of esophageal cancer requires meticulous superior mediastinal lymphadenectomy, in addition to esophagectomy, because superior mediastinal lymph node metastases are common in esophageal cancer. When preserving the tracheal branches of the left recurrent laryngeal nerve (RLN), good anatomical understanding is required for confirmation of the positional relationships between the courses of lymphatic vessels, lymph node distribution, and the left RLN and its tracheal branches. We performed a detailed anatomical examination of these relationships. METHODS: Macroscopic anatomical observation and histological examination was performed on cadavers. In addition to hematoxylin and eosin staining, immunostaining using antipodoplanin antibody D2-40 (podoplanin) was performed to identify the lymphatic vessels. RESULTS: The tracheal branches of the left RLN were clearly observed, but no lymphatic vessels crossing the ventral or dorsal side of the branches were identified either macro-anatomically or histologically. CONCLUSION: No complex lymphatic network structure straddling the plane composed of tracheal branches of the left RLN was found in the left superior mediastinum. This suggests that dissection of the lymph nodes around the left RLN via the pneumomediastinum method using the left cervical approach may allow preservation of the tracheal branches of the left RLN by maintaining dissection accuracy.

Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors.

Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.

Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.

Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors.

Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.

Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3.

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.

Synthesis and evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting Janus kinase 3.

Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.

[Curative dissection of paraaortic lymph node metastases after operation for ascending colon cancer].

In October 2007, a 69-year-old woman underwent right hemicolectomy and D3 lymph node dissection for the treatment of adenocarcinoma (type 2, por2]tub2, pSS, pN3, fStage IIIb). Serum carcinoembryonic antigen (CEA) concentration was 152.8 ng/mL preoperation, but returned to normal after the operation. Adjuvant chemotherapy using 450 mg/day UFT-E was added. Computed tomography (CT) examination revealed a swollen paraaortic lymph node 3 months after the operation, while serum CEA concentration had increased to 92.7 ng/mL. After the chemotherapy was changed to FOLFOX, the paraaortic lymph node shrank and serum CEA concentration decreased. However, after 6 courses, serum CEA concentration increased again and bevacizumab-FOLFIRI therapy was initiated. After 3 courses of bevacizumab-FOLFIRI were not effective, paraaortic lymph node dissection was performed in February 2009. Pathological examination of the resected specimen showed metastatic adenocarcinoma. At present, the patient is alive without any signs of recurrence. Although the effectiveness of chemotherapy for paraaortic lymph node metastasis of colorectal cancer has been described, complete cure has not been reported. Thus, surgical resection has the potential to cure solitary recurrence of paraaortic lymph node metastasis, and therefore, should be considered in the treatment of such cases.

[A case report of gastric cancer consisting predominantly of undifferentiated carcinoma].

We encountered a rare case of gastric cancer consisting predominantly of undifferentiated carcinoma.The patient was a 64-year-old man who underwent various tests because of symptoms of dysphagia in September 2012.We found a subcircumferential type II tumor at the gastroesophageal junction.A total gastrectomy, splenectomy, and Rouxen-Y reconstruction were performed.Adhesiotomy was also performed for the ileus on postoperative day (POD)2.The patient subsequently experienced septic shock with disseminated intravascular coagulation (DIC) and acute kidney failure due to complications of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and MRSA colitis.As a consequence, the patient required respiratory management and continuous hemodiafiltration (CHDF). In addition, the patient experienced hemorrhage from the Roux-en-Y-anastomotic site in the contact with the ileus tube during treatment for septicemia on POD14, which was resolved with endoscopic treatment.Moreover, a cholecystectomy was performed on POD52 for gangrenous cholecystitis.The patient's progress was satisfactory.The pathology results revealed an undifferentiated carcinoma with the following characteristics: pT4a (SE), ly1, v0, pPM1, pDM0, type 2, 80 × 75 mm, UE, Less.In addition, immunostaining results revealed a tumor consisting of at least 90% of undifferentiated carcinoma tissue.Four months after surgery, local recurrence at the site of the esophagojejunostomy, disseminated recurrence around the left kidney, and metastases in the left adrenal gland appeared. The partial response (PR) was maintained by treatment with CPT-11+ cisplatin (CDDP) + trastuzumab.However, left adrenalectomy was performed 1 year and 4 months after the initial surgery was performed for metastasis to the left adrenal gland that started 10 months after surgery.One year and 10 months after the initial surgery, the patient continues to receive treatment with trastuzumab and has not exhibited signs of recurrence.

[Two cases of giant retroperitoneal liposarcoma].

The first patient was of a 71-year-old woman who was examined for abdominal protuberance. Computed tomography (CT) and magnetic resonanc e imaging(MRI)revealed a giant tumor almost occupying the entire abdomen. En-bloc resection was performed. The tumor was 30 cm in size and weighed 6,500 g. The histological diagnosis was a well-differentiated liposarcoma. The second patient was a 72-year-old woman who visited our hospital after she had been diagnosed with an abdominal tumor by her family doctor. CT and MRI revealed a massive tumor involving various components. The tumor had invaded the left ureter and descending colon; therefore, we performed tumorectomy, left nephrectomy, and descending colectomy. The histopathological findings indicated a well-differentiated, myxoid, pleomorphic liposarcoma. The tumor recurred 4, 5, and 7 years after the first operation. By the fourth operation, the histological subtype of the tumor had changed to a dedifferentiated type.

Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

BACKGROUND: The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. METHODS: This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. RESULTS: Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. CONCLUSIONS: The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

Potential benefit of the cathepsin S inhibitor, ASP1617, as a treatment for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the dysregulation of various cell types and immunological pathways. Autoantibodies play an important role in its pathogenesis. The presence of autoantibodies suggests that self-antigen presentation through major histocompatibility complex (MHC) class II on antigen presenting cells is involved in the pathogenesis of autoimmune diseases, including SLE. Cathepsin S (CatS) is a key protease for antigen peptide loading onto lysosomal/endosomal MHC class II molecules through invariant chain degradation to promote antigen presentation. Inhibition of CatS is therefore expected to suppress antigen presentation via MHC class II, T and B cell activation, and antibody production from B cells. Here, we report the pharmacological profile of ASP1617, a novel CatS inhibitor. ASP1617 induced invariant chain accumulation and decreased the expression level of MHC class ΙΙ on the cell surface in both mouse and human B cells. Further, ASP1617 prevented DO11.10 mice T cell proliferation to ovalbumin antigen. We investigated the effects of ASP1617 and mycophenolate mofetil (MMF) on the development of lupus-like nephritis in NZB/W F1 mice, a widely used SLE mouse model. Oral administration of ASP1617 suppressed anti-dsDNA IgG, prevented progression of lupus-like glomerulonephritis, and significantly prevented proteinuria excretion. In contrast, MMF did not suppress anti-dsDNA IgG. Further, we found that plasma and/or urine CatS levels were increased in specimens from NZB/W F1 mice and several SLE patients. These results indicate that CatS may be an attractive therapeutic target for the treatment of SLE.

[A case of long-term survival after curative resection of advanced rectal cancer treated by pre-operative chemoradiotherapy].

We report a long-term survival case of rectal cancer that was initially thought unresectable treated with chemoradiotherapy (CRT). The patient was a 50s female with advanced rectal cancer and liver metastasis. The primary tumor was expanded locally and made abscess around the rectum. We evaluated the primary lesion as unresectable, and we performed CRT after colostomy. After radiation therapy (total 60 Gy) and chemotherapy with S-1 (3 courses), the primary tumor was remarkably reduced. The liver metastasis showed a progressive growth in size but not in number. She underwent complete resection of rectal tumor and partial resection of metastatic liver tumor. Postoperative course was uneventful, and she is alive without a recurrence for 5 years after the surgery.

[A case of herpetic meningoencephalitis associated with massive intracerebral hemorrhage during acyclovir treatment: a rare complication].

We report a case of a 35-year-old female with herpetic meningoencephalitis confirmed by polymerase chain reaction and immunohistochemical study for herpes simplex virus-1 accompanied with a massive intracerebral hematoma as a complication. A hematoma localized at the medial temporal lobe and the medial frontal lobe occurred on the 11th day after initiation of acyclovir treatment. She subsequently required emergency surgery for temporal lobectomy, as well as hematoma and external decompression. Intracerebral hematoma with MR imaging showed gyral pattern along the cortex of the medial temporal lobe and the base of the medial frontal lobe. We speculate that the hemorrhage occurred by rupture of small vessels affected by vasculitis in addition to hypertension caused by increased intracranial pressure. We therefore emphasize the risk of intracerebral hemorrhage at an early stage or during acyclovir treatment, especially during one or two weeks after initiation of the treatment, and the necessity of careful observation during these periods.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.

Illusory Oscillation of the Central Rotation Axis.

In this study, we report a novel visual illusion for rotational motion, in which the central rotation axis of a partially invisible (apparent) square is perceived as exhibiting oscillatory rotation. To investigate the cause of this illusion, we measured the central position of a static apparent shape using an adjustment method (Experiment 1) and manipulated the speed of the rotating apparent square to test whether the illusion could be cancelled out by counteracting rotation using a constant method (Experiment 2). The results revealed that the perceived central position of a static apparent shape was shifted toward the outside. The shifted position depended on the orientation of the stimulus, and its position was arranged as if it was moving in a circular trajectory. In addition, the cancellation technique using counteracting rotation was successful, and cancellation of faster rotation required a greater radius of counteracting rotation. These results indicated that the illusion is induced by an interaction between illusory shifts of the central position of the static shape and the summation of motion vectors or motion momentum (e.g., centrifugal force) derived from shape representation by perceptual completion.

Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I.

A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.